Subject: RFA HG-90-03 from NIH Guide of September 7th.
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Wed, 05 Sep 90 14:40 EST

Hello,
   Another one for the NIH Listserver. Please post this one as:
     RFAHG-90-03.090790
  Thanks.   Dottie
 ---------------------------- Text of forwarded message -----------------------
 
FEASIBILITY STUDIES FOR LARGE-SCALE DNA SEQUENCING OF
REGIONS OF HIGH BIOLOGICAL INTEREST
 
RFA AVAILABLE:  HG-90-03
 
P.T. 34; K.W. 0755045, 1004000, 0755018
 
National Center For Human Genome Research
 
Letter of Intent Receipt Date:  October 15, 1990
Application Receipt Date:  December 3, 1990
 
The National Center for Human Genome Research (NCHGR)
invites applications for assistance awards to support
feasibility studies using advanced state-of-the-art DNA
sequencing technology to accomplish large-scale sequencing
projects at a higher rate and lower cost than is currently
possible.
 
This program is described in the Catalog of Federal Domestic
Assistance No. 13.172.  Awards will be made under the
authority of the Public Health Service Act, Sections 301
(Public Law 78-410, as amended 42 U.S.C. 241) and
administered under PHS grants policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program
is not subject to the intergovernmental review requirement
of Executive Order 12373 or to Health System Agency review.
 
BACKGROUND
 
The NCHGR sponsors basic and applied research concerned with
the development and application of new technologies for the
characterization and analysis of the human genome and the
genomes of important model organisms.  The activities
encompassed by the NCHGR program include genetic and
physical mapping, DNA sequencing, and informatics related to
mapping and sequencing.  The NCHGR, in conjunction with the
Department of Energy, recently formulated a five-year plan
that identifies areas where further research, including new
technology development, is needed before the
characterization of the human and other genomes can proceed
to the degree envisioned by the scientific community.
 
With respect to sequencing megabase regions of DNA, it is
clear that rates of sequence acquisition achievable today
must be increased at least 10- to 100-fold, and DNA
sequencing costs must be reduced at least 10-fold before
large-scale sequencing, on the order of a human chromosome,
can be considered.  Current technology for DNA sequencing
includes both manual and automated methods.  Sequencing DNA
by these methods is estimated to cost between $2 and $5
(total cost) per base pair.  However, currently available
sequencing techniques and strategies have not been tested on
a large scale.  Thus, it is possible that current or
improved methods, when used at the megabase level, and when
combined with economies of scale, new strategies, improved
automation, and/or new technologies, will significantly
lower the cost of DNA sequencing.  The purpose of this
Request for Applications (RFA)
is to support investigator-initiated research projects that
will extend the limits of advanced state-of-the-art
technology considerably further than has yet been attempted.
 
DEFINITION OF LARGE-SCALE SEQUENCING
 
The Program Advisory Committee on the Human Genome has
suggested that, at the present time, a reasonable definition
of a "large-scale sequencing project" is one that attempts
to determine on the order of three megabase pairs of
(largely) contiguous sequence in three years (by comparison,
the largest DNA sequence completed to date is a viral genome
of 240 kilobase pairs, work that took several years to
complete).  Continuity is an important characteristic of the
DNA sequence to be obtained;  the scientific problems that
arise in considering sequencing a one-megabase region are
different from those involved in sequencing 1000 one-
kilobase regions.  The Committee estimated that a rate of 2-
5 megabase pairs of DNA sequence per year in the subsequent
years should be attainable.  Similarly, reduction of the
cost of DNA sequencing to approximately $0.75 per base pair
within three years and to $0.50 per base pair within five
years was recommended to be a reasonable guide.  As these
levels are well beyond anything that has been achieved to
date, applicants are encouraged to consider them as
guidelines.   The NCHGR encourages discussion of these
guidelines by applicants, including an estimate of whether
they can be achieved.
 
DATA MANAGEMENT
 
Another essential component of DNA sequencing projects that
also needs to be investigated on a large scale is data
management.  Although software and database packages are
currently available for acquisition and assembly of DNA
sequence, they have been developed for relatively small-
scale applications.  Thus, it is not known whether any of
these will be adequate for use in megabase sequencing
projects.  It is understood that different sequencing
strategies will have different data handling needs and,
therefore, no one solution to data management problems for
large-scale sequencing is likely.
 
While, in the long run, software may have to be developed
for interpretation of the large segments of DNA sequence
generated by the human genome project, the informatics
priorities for this RFA will be primarily directed toward
the design, development, and testing of software for data
acquisition, assembly, and management.
 
RESEARCH SCOPE
 
Projects responsive to this RFA should test hypotheses and
new research strategies designed to yield information on the
feasibility of determining large amounts of DNA sequence
rapidly and in a cost-effective manner.  It is anticipated
that such projects will involve an integrated approach that
addresses a number of identifiable aspects of the problem,
including:
 
o The biological materials to be sequenced, e.g.,
genomic DNA or overlapping clones representing a
megabase-sized region.  Applicants are encouraged
to select DNA comprising regions of high
biological interest;
 
o Scale-up of DNA sequencing technology to allow
large-scale, high-throughput, and low-cost
acquisition of DNA sequence data.  Note: in order
to have a uniform approach for estimating the cost
of sequencing, applicants should calculate the
cost per base of finished DNA sequence ready for
publication and/or submission to a public
database.  The cost figure should include all
direct and indirect expenses, starting either
directly with the DNA of the organism  or with
appropriately large fragments (YAC or cosmid
clones) and ending with the final finished
sequence.  Neither the costs of any necessary
laboratory renovation nor the costs associated
with the interpretation of DNA sequence data
should be considered as a part of the per base
cost of sequence determination;
 
o Types of errors and rates of error that will occur
in large-scale DNA sequencing, and a discussion of
what level of error will be acceptable;
 
o Overall strategies, including quality control
systems, and plans for organizing the research
group;
 
o Systems for data acquisition, data management,
sequence assembly, and error estimation.
 
DATA RELEASE
 
The policy of the U.S. Public Health Service (PHS) states
that "when resources are developed with PHS funds and the
associated research findings have been published . . . it is
essential that they be made readily available for research
purposes to the scientific community."  Applicants will be
expected to follow this policy.  Generating large amounts of
DNA sequence will raise additional questions with respect to
data release and public accessibility to DNA sequence data
because much of this data will never be published in
journals or will not be published in its entirety.  The
NCHGR considers the timely release of data to the scientific
community to be critical and encourages applicants to
release all sequence data, including those that are not
published,  to a public database in a timely fashion.  This
is an area of active discussion within the scientific
community.  Although it will not be used as a review
criteria, the NCHGR is interested in the
investigator's analysis and evaluation of issues related to
the timely release of data, such as a timetable for data
release, the criteria for "finished" DNA sequence (i.e.,
sequence that is ready to be publicly released), and the
intervals (e.g., number of nucleotides or number of months)
at which data will be released.
 
MECHANISM OF SUPPORT
 
Support for this program will be through research grants
(R01s). Applicants may request up to five years of support.
For grants awarded for more than three years, competitive
renewals will be due at the end of the third year to allow a
determination of whether the project is satisfactorily
meeting its stated objectives.  As a result of that review,
funds may be continued at the level recommended or reduced
to phase out the project by the end of the original project
period.
 
An annual meeting is being planned to assist grantees receiving
funds under this RFA in maintaining communication with other
investigators working on the development of large-scale DNA
sequencing methods and in obtaining rapid access to those
developments.  Funds for
travel to this
meeting for as many as two investigators can be requested.
 
The total amount of support available for grants under this RFA
(approximately $6 million) is
contingent upon the appropriation of funds for this purpose.
It is anticipated that up to three awards will be made
during fiscal year 1991.  There is no set limit on the size
of each award.  Rather, each investigator should propose a
budget adequate to accomplish the work proposed.  The number
of awards is contingent
upon the quality of the applications received; if there are
a large number of meritorious applications, consideration
will be given to increasing the number of awards.  It is
possible that additional RFAs soliciting applications on
this topic may be published in the future.
 
LETTER OF INTENT
 
It is strongly recommended that potential applicants contact
NCHGR staff to discuss research objectives.  Potential
applicants are asked to submit a letter of intent by October
15, 1990.  This letter should include a descriptive title of
the proposed research, names of principal investigators and
other key investigators and their institutions.  The
letter of intent is requested in order to provide an
indication of the number and scope of applications to be
reviewed.  The letter of intent does not commit the sender
to submit an application, nor is it a requirement for
submission of an application.  Letters of intent should be
sent directly to:
 
Dr. Jane L. Peterson
Chief, Research Centers Branch
National Center for Human Genome Research
Building 38A, Room 610
National Institutes of Health
Bethesda, MD  20892
Telephone:  (301) 496-7531
E-mail:  [email-masked]; [email-masked]
 
APPLICATION AND REVIEW PROCEDURES
 
Applications in response to this announcement will be
reviewed in accordance with the usual NIH peer review
procedures.  If the application submitted in response to
this RFA is substantially similar to a research grant
application already submitted to the NIH for review, but has
not yet been reviewed, the applicant will be asked to
withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not
be allowed, nor will essentially identical applications be
reviewed by different review committees.  Therefore, an
application cannot be submitted in response to this RFA
which is essentially identical to one that has already been
reviewed.  This does not preclude the submission of
substantial revisions of applications already reviewed, but
such applications must include an Introduction addressing
the previous critique.
 
Applications will first be screened for responsiveness to
this RFA by NIH staff.  Those deemed nonresponsive will be
returned to the applicant.  If a large number of responsive
applications is received, they will undergo a preliminary
peer review to identify the most meritorious ones.
Applications that are deemed non-competitive by this peer
review will receive only a brief critique and will not be
reviewed further.  The remaining applications will be
reviewed for scientific and technical merit by an initial
review group (IRG) assembled by the Office of Scientific
Review, NCHGR.  A second level of review will be conducted
by a national advisory council.  Review criteria include the
following:
 
o Overall scientific and technical merit of the
research;
 
o The potential for the proposed work for
attaining the research objectives outlined in
this RFA;
 
o Training, experience, research competence,
and dedication of the investigator(s);
 
o Adequacy of available facilities;
 
o Provision for the protection of human
subjects and the humane care of animals; and
 
o Appropriateness of the requested budget for
the work proposed.
 
Applications should be submitted using the form PHS 398
(rev. 10/88).  The RFA label available in the revised
application kit MUST be affixed to the bottom of the face
page.  Failure to use this label could result in delayed
processing of the application such that it may not reach the
review committee in time for review.  Application kits are available in
the business or grants office at most academic or research
institutions, or from the Division of Research Grants,
National Institutes of Health.  Applications will be
accepted in accordance with the following schedule:
 
TIMETABLE:
 
Receipt Date:                 December 3, 1990
IRG Review:                   Feb/March, 1991
Council Review:               May 1991
Earliest Funding Date:        July 1991
 
It is essential that applicants type "Feasibility Studies
for Large Scale DNA Sequencing of Regions of High Biological
Interest" and the RFA number HG-90-03 on line 2 on the face
page of the application form.  The original and four copies
of the application should be submitted to the following
office:
 
Grant Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
To expedite the review process, it is important to submit
two copies of your application directly to:
 
Office of Scientific Review
National Center for Human Genome Research
Building 38A, Room 604
National Institutes of Health
Bethesda, MD  20892
 
Funding decisions will be based on recommendations of the
initial review group and the advisory council regarding the
scientific merit and program relevance.  For more
information and the complete RFA, please contact:
 
Dr. Jane L. Peterson
Chief, Research Centers Branch
National Center for Human Genome Research
Building 38A, Room 610
National Institutes of Health
Bethesda, MD  20892
Telephone:  (301) 496-7531
E-mail:  [email-masked]; [email-masked]